A multicenter study led by Memorial Sloan-Kettering Cancer Center investigators concluded that treatment with a new targeted therapy called PLX4032 resulted in significant tumor shrinkage in 80 percent of patients with advanced melanoma.
“We never before had a specific target in melanoma that we could attack,” said Memorial Sloan-Kettering medical oncologist Paul B. Chapman, senior author of the study, published in the New England Journal of Medicine. “But we now know half of melanomas depend on a mutated gene called BRAF for their growth. PLX4032 inhibits BRAF at the cellular level and shuts off these tumors. We have seen many tumors shrink rapidly and, in some patients, quality of life improved dramatically.”
The phase I trial determined the maximum dose of the drug that could be given without adverse side effects and was followed by an extension of the trial, a phase II trial, at that recommended dose. Fifty-five patients were enrolled in the first portion of the study. Screening for BRAF mutations was not a requirement for initial entry, but as the trial progressed, an increasing percentage of patients were identified as having the mutation. Later, 32 patients with BRAF-mutated melanomas were added to the second phase.
In the phase I group, ten partial responses and one complete response were noted among 15 melanoma patients with BRAF mutations who were treated with moderate to full doses of the drug. In the extension group, two complete and 24 partial responses were seen among the 32 patients treated with a full dose of drug. To date, 16 of 32 patients are still in the study. The side effects were minor and did not result in any patients leaving the study.
Dr. Chapman is now leading a phase III trial of PLX4032, which completed accrual extremely quickly, in less than a year. “While we see most tumors shrink, the tumor responses are not always long-lasting,” he explained. “We don’t yet know if treatment improves overall survival of melanoma patients. However, our new understanding of the molecular pathways driving melanoma provides a strong rationale to combine PLX4032 with other new antimelanoma drugs.”
A restricted diet may help reduce symptoms of attention-deficit hyperactivity disorder in children, according to a study in the Lancet.
Hypothesizing that ADHD might be a hypersensitivity disorder, researchers randomized 100 children aged 4 to 8 years with ADHD to a diet or control group. The intervention group ate an individually designed restricted diet consisting of rice, meat, vegetables, pears, water, potatoes, fruits, and wheat. After 5 weeks, 64% of children in the restricted diet group showed a clinical improvement of at least 40% on ADHD scores.
The 30 children with clinical improvement moved on to the challenge phase — having either three high-IgG or three low-IgG foods (based on individual blood tests) reintroduced into their diet for 2 weeks before switching to the other IgG group. Most children (63%) experienced a relapse of ADHD behavior during this phase, regardless of whether they were receiving high- or low-IgG food components.
A commentator says that the results provide “evidence against the benefit of using IgG blood levels (a common practice in complementary medicine) to determine which foods are triggering ADHD symptoms.” She says that children with ADHD may go on a restricted diet for 2 to 5 weeks, and then reintroduce one food per week.
Benefit was modest; longer-term efficacy and safety data are needed.
Because patients with irritable bowel syndrome (IBS) can have alterations in bacterial bowel flora, antibiotic therapies have been proposed. To investigate whether antibiotic therapy is effective, industry-supported researchers randomized 1260 IBS patients with abdominal pain and bloating (but without constipation) to receive 2-week courses of either rifaximin (Xifaxan) or placebo. Rifaximin is a minimally absorbed antibiotic that is FDA-approved for treatment of travelers’ diarrhea and prevention of hepatic encephalopathy.
The primary endpoint (patient-reported “adequate relief” of IBS symptoms during at least 2 of the 4 weeks following treatment) was noted by 41% of rifaximin recipients and by 32% of placebo recipients — a significant difference. Outcomes were similar for relief of bloating specifically. During 6 additional weeks of observation, the proportion of responders declined in both groups but remained higher in the rifaximin group than in the placebo group. No serious adverse effects occurred.
Comment: A 2-week course of rifaximin relieved IBS symptoms in some patients during the month after treatment. The 9-percentage-point difference in response between rifaximin and placebo means that 11 patients must be treated to benefit 1 patient. Because benefit was modest, follow-up was brief in this chronic condition, and concern exists that widespread use of rifaximin could promote bacterial resistance, longer-term efficacy and safety data are necessary before rifaximin can be added to the list of IBS treatments.
— Allan S. Brett, MD
Published in Journal Watch General Medicine February 3, 2011